Humoral Research Articles

Current Advance and Future of mRNA Vaccine in Cancer Therapy

After years of development, cancer vaccines have gradually become an important part of tumor immunotherapy, and have shown a more rapid development momentum under the background of the current era. The vaccine has the advantages of high efficiency, safety, rapid development potential, cost-effectiveness, etc. In recent years, with the continuous improvement of mRNA technology, relevant technologies in the field of mRNA molecules have also made breakthrough progress, and mRNA vaccines have achieved certain results in cancer treatment. Compared with traditional vaccines, mRNA vaccines can induce the body to produce humoral immunity and cellular immunity at the same time, and the research and development cycle is short, the cost is low, and it can quickly develop candidate vaccines to deal with virus mutation, which is conducive to cancer control. mRNA vaccines have become a current research hotspot and have wide application prospects in the prevention and treatment of tumors and infectious diseases. This article comprehensively discusses the structural characteristics, types, unique advantages and future prospects of mRNA vaccines, in order to help understand the vaccine function and clinical application of mRNA, provide a direction for the development of mRNA drugs, and expect that mRNA cancer vaccines will be used in clinic as soon as possible to benefit patients.

Humoral Immunity Profiling to Pandemic and Bat‐Derived Coronavirus Variants: A Geographical Comparison

AbstractDynamic pathogen exposure may impact the immunological response to SARS‐CoV‐2 (SCV2). One potential explanation for the lack of severe SCV2‐related morbidity and mortality in Southeast Asia is prior exposure to related betacoronaviruses. Recent discoveries of SCV2‐related betacoronaviruses from horseshoe bats (Rhinolophus sinicus) in Thailand, Laos, and Cambodia suggest the potential for bat‐to‐human spillover exposures in the region. In this work, serum antibodies to protein constructs from SCV2 and a representative bat coronavirus isolated in Cambodia (RshSTT182) are measured in pre‐pandemic Cambodian human sera using ELISA assays. Of 293 Cambodian samples tested (N = 131 with acute malaria, n = 162 with acute undifferentiated febrile illness), 32 (10.9%) are seropositive for SCV2 based on established Spike and receptor‐binding domain (RBD) cutoffs. Within SCV2 seropositive samples, 16 (50%) have higher antibody levels to antigens from the representative virus RshSTT182 versus SCV2 antigens; competitive binding ELISA assays demonstrate inhibition of reactivity to SCV2 Spike after pre‐incubation with RshSTT182 Spike. Surrogate virus neutralization tests demonstrate that 8/30 (26.7%) SCV2 ELISA positive pre‐pandemic Cambodian samples have neutralizing activity against SCV2, while 14/30 (46.7%) have activity against other SCV2‐related betacoronaviruses. These data suggest that exposure to related betacoronaviruses may elicit cross‐reactive immunity to SCV2 prior to the global pandemic.

Characterization of anti-AAV2 neutralizing antibody levels in sheep prior to and following intravitreal AAV2.7m8 injection

AbstractGene augmentation therapy is a promising treatment for incurable, blinding inherited retinal diseases, and intravitreal delivery is being studied as a safe alternative to subretinal injections. Adeno-Associated Viruses (AAV) are commonly-used vectors for ocular gene augmentation therapy. Naturally occurring pre-operative exposure and infection with AAV could result in presence of neutralizing antibodies (NAB’s) in patients’ serum, and may affect the safety and efficacy of treatment. Our aim was to characterize the humoral response against AAV pre- and post-intravitreal delivery of AAV2.7m8 vectors in a naturally-occurring sheep model of CNGA3 achromatopsia. Serial serum neutralization assays were performed to screen sheep for pre-exiting anti-AAV2 NAB’s, and to assess the effect of intravitreal AAV2.7m8 injection on post-operative NAB titers and intraocular inflammation in sheep. The effect of viral dose and transgene type were also assessed. Serological screening revealed pre-operative seropositivity in 21.4% of animals, with age being a risk factor for the presence of anti-AAV2 NAB’s. NAB titers increased following intravitreal AAV administration in the majority of sheep. There was no significant difference in the degree of post-operative serum neutralization between pre-operatively seronegative sheep and those with pre-existing antibodies. However, only sheep with pre-existing antibodies presented with signs of post-operative inflammation. We conclude that pre-existing anti-AAV2 NAB’s do not affect the level of post-operative NAB titers; however, they increase the risk of post-operative ocular inflammation. Our results could have implications for the management of AAV-mediated ocular gene therapies, a technology being increasingly studied and used in patients.

Large Clostridial Toxins: A Brief Review and Insights into Antigen Design for Veterinary Vaccine Development.

The group of large clostridial toxins (LCTs) includes toxins A (TcdA) and B (TcdB) from Clostridioides difficile, hemorrhagic and lethal toxins from Paeniclostridium sordellii, alpha toxin from Clostridium novyi (TcnA), and cytotoxin from Clostridium perfringens. These toxins are associated with severe pathologies in livestock, including gas gangrene (P. sordellii and C. novyi), infectious necrotic hepatitis (C. novyi), avian necrotic enteritis (C. perfringens), and enterocolitis (C. difficile). Immunoprophylaxis is crucial for controlling these diseases, but traditional vaccines face production challenges, such as labor-intensive processes, and often exhibit low immunogenicity. This has led to increased interest in recombinant vaccines. While TcdA and TcdB are well-studied for human immunization, other LCTs remain poorly characterized and require further investigation. Therefore, this study emphasizes the importance of understanding lesser-explored toxins and proposes using immunoinformatics to identify their immunodominant regions. By mapping these regions using silico tools and considering their homology with TcdA and TcdB, the study aims to guide future research in veterinary vaccinology. It also explores alternatives to overcome the limitations of conventional and recombinant vaccines, offering guidelines for developing more effective vaccination strategies against severe infections in animals.

Self-Adjuvanting Adenoviral Nanovaccine for Effective T-Cell-Mediated Immunity and Long-Lasting Memory Cell Activation against Tuberculosis.

An enhanced vaccine is immediately required to swap the more than 100 year-old bacillus Calmette-Guerin (BCG) vaccine against tuberculosis. Here, trimethyl chitosan-loaded inactivated Mycobacterium smegmatis (MST), along with potent adenovirus hexon protein (AdHP), and toll-like receptor (TLR)-1/2 as a nanovaccine, was developed against tuberculosis (TB). The nanoformulation increased the bioavailability of MST and elicited the targeting ability. Nanovaccines have a size range of 183.5 ± 9.5 nm with a spherical morphology and uniform distribution. The nanovaccine exhibited a higher release of antigen in acidic pH, and this is mainly due to protonation of ionizable groups in polymeric materials. The nanovaccine facilitated the effective cellular uptake of bone-marrow-derived dendritic cells and progressive endosomal escape in a shorter period. In vitro analyses indicated that the nanovaccine activated cytokine and T-cell production and also assisted in humoral immunity by producing antibodies. The nanovaccine was able to induce more cellular and humoral memory cells and a better protective immune response. Nanomaterials effectively delivered the MST, AdHP, and TLR1/2 antigens to the major histocompatibility complex class I and II pathways to generate protective cytotoxic CD8+ and CD4+ T-cells. In vivo experiments, compared with free MST and BCG, showed that mice immunized with the nanovaccine induced more specific CD4+, CD8+, and memory T-cell activations. Overall, the fabricated nanovaccine was able to control the release of antigens and adjuvants and enhance memory cell activation and humoral immunity against TB.

Fecal microbiota transplantation from protozoa-exposed donors downregulates immune response in a germ-free mouse model, its role in immune response and physiology of the intestine.

Intestinal parasites are part of the intestinal ecosystem and have been shown to establish close interactions with the intestinal microbiota. However, little is known about the influence of intestinal protozoa on the regulation of the immune response. In this study, we analyzed the regulation of the immune response of germ-free mice transplanted with fecal microbiota (FMT) from individuals with multiple parasitic protozoans (P) and non-parasitized individuals (NP). We determined the production of intestinal cytokines, the lymphocyte populations in both the colon and the spleen, and the genetic expression of markers of intestinal epithelial integrity. We observed a general downregulation of the intestinal immune response in mice receiving FMT-P. We found significantly lower intestinal production of the cytokines IL-6, TNF, IFN-γ, MCP-1, IL-10, and IL-12 in the FMT-P. Furthermore, a significant decrease in the proportion of CD3+, CD4+, and Foxp3+ T regulatory cells (Treg) was observed in both, the colon and spleen with FMT-P in contrast to FMT-NP. We also found that in FMT-P mice there was a significant decrease in tjp1 expression in all three regions of the small intestine; ocln in the ileum; reg3γ in the duodenum and relmβ in both the duodenum and ileum. We also found an increase in colonic mucus layer thickness in mice colonized with FMT-P in contrast with FMT-NP. Finally, our results suggest that gut protozoa, such as Blastocystis hominis, Entamoeba coli, Endolimax nana, Entamoeba histolytica/E. dispar, Iodamoeba bütschlii, and Chilomastix mesnili consortia affect the immunoinflammatory state and induce functional changes in the intestine via the gut microbiota. Likewise, it allows us to establish an FMT model in germ-free mice as a viable alternative to explore the effects that exposure to intestinal parasites could have on the immune response in humans.

Human cellular restriction factors that target SARS-CoV-2 replication

Millions of people have died and a worldwide economic catastrophe has been brought on by the coronavirus disease 2019 (COVID-19) pandemic. Infections caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may presently be treated with less than 10 antiviral drugs such as Remdesivir. The need for medical intervention due to sickness has led to unprecedented research efforts to study the biology of coronaviruses. Additionally, there is a strong likelihood that coronaviruses will cause pandemics in the future. All viruses cannot replicate optimally due to host restriction factors. Given that they are genetically more stable than viral targets and may be shared by similar viruses, these antiviral host factors provide appealing targets for antiviral treatment. The identification of antiviral host factors that are a component of human innate immunity and that prevent the completion of the SARS-CoV-2 life cycle has been made possible by the deployment of several “omics” technologies. In this review, we provide an overview of the antiviral host factors that limit the replication of SARS-CoV-2 in this, which were mostly discovered using functional genetic and interactome screening. Important cellular mechanisms for the SARS-CoV-2 life cycle are covered. Finally, we highlight host restriction factors that could be targeted by clinically approved molecules and the induction of these factors as potential antiviral therapies for COVID-19.

Spleen-Targeted mRNA Vaccine Doped with Manganese Adjuvant for Robust Anticancer Immunity In Vivo.

The successful application of mRNA vaccines in preventing and treating infectious diseases highlights their potential as therapeutic vaccines for cancer treatment. However, unlike infectious diseases, effective antitumor therapy, particularly for solid tumors, necessitates the activation of more powerful cellular and humoral immunity to achieve clinical efficacy. Here, we report a spleen-targeted mRNA vaccine (Mn@mRNA-LNP) designed to deliver tumor antigen-encoding mRNA and manganese adjuvant (Mn2+) simultaneously to dendritic cells (DCs) in the spleen. This delivery system promotes DC maturation and surface antigen presentation and stimulates the production of cytotoxic T cells. Additionally, Mn2+ codelivered in the system serves as a safe and effective immune adjuvant, activating the stimulator of interferon genes (STING) signaling pathway and promoting the secretion of type I interferon, further enhancing the antigen-specific T cell responses. Mn@mRNA-LNP effectively inhibits tumor progression in established melanoma and colon tumor models as well as in a model of tumor recurrence after resection. Notably, the combination of Mn@mRNA-LNP with immune checkpoint inhibitors further enhances complete tumor suppression and prolonged the overall survival in mice. Overall, this "All-in-One" mRNA vaccine significantly boosts antitumor immunity responses by improving spleen targeting and immune activation, providing an attractive strategy for the future clinical translation of therapeutic mRNA vaccines.

Sex-specific immune responses to COVID-19 vaccination in end-stage renal disease patients

Abstract Background End-stage renal disease (ESRD) patients have muted memory B cell formation and reduced humoral responses to COVID-19 vaccination; however, early innate immune responses have yet to be characterized. Sex-stratification is also limited in COVID-19 vaccination research. Methods We collected blood before (BD1) and 1-4 days post-dose 1 (PD1) of BNT162b2 vaccination for RNA-sequencing in ESRD patients (n = 35 BD1; 18 PD1) and healthy controls (HC) (n = 31 BD1; 30 PD1). Additionally, 20 plasma cytokines were quantified in ESRD patients (n = 39 BD1, 35 PD1) and HC (34 BD1, 15 PD1). Results Transcriptional profiling of vaccine responses identified 125 significantly differentially expressed genes (DEG) (padj<0.04) in ESRD patients and 107 DEGs (padj<0.05) in HC. 71 DEGs were shared, 54 unique to ESRD, and 36 unique to HC. DEG, pathway analyses, and cytokine responses in the combined dataset showed ESRD patients were more inflamed than HC at baseline, with an elevated inflammatory cytokine profile compared to HC. These results were driven by female ESRD patients where IL-2, IL-10, and IP-10 were more significant in females (p < 0.001) compared to males (p < 0.01). While IL-6, IFN-γ, IL-13, eotaxin, were exclusively associated in females (p < 0.05). Healthy females also had a stronger immunological response to vaccination compared to healthy males. Conclusions Despite baseline inflammation, ESRD patients were able to mount similar early immune responses to vaccination as HC, with females in both populations more reactogenic than males. Sex-stratification is recommended for ongoing immunological research to better understand unique responses to COVID-19 vaccination. Key messages • End-stage renal disease patients have similar early innate immune responses to COVID-19 vaccination as healthy controls. • Sex-stratification is important to identify unique immunological responses that may be leveraged for sex-specific vaccination strategies.

2.I. Scientific session: Addressing vaccine hesitancy: from understanding determinants to implementing targeted strategies

Abstract Supported by NextGenerationEU (no. PE00000007) and EU4Health (VAXaction), the workshop will present a pan-European perspective on vaccine hesitancy and the effectiveness of counteracting interventions, especially when facing potentially pandemic infectious threats. Analysing human responses to epidemics is crucial to improve mathematical disease modelling and develop strategies to monitor behaviours during outbreaks, including assessing levels of vaccine hesitancy. This session will explore the multifaceted issue of vaccine hesitancy, which remains a significant barrier to achieving optimal vaccination coverage and is identified as one of the top threats to global health. By integrating theoretical frameworks with practical applications, the workshop aims to present a comprehensive overview of strategies employed to mitigate hesitancy across various demographics and regions. The first presentation will cover a thorough overview of the strategies employed to counteract vaccine hesitancy, leveraging existing infrastructure, health promotion policies, and educational initiatives. It will also explore the role of digital health tools and regulatory measures, such as health passes and nudging techniques, in enhancing vaccination uptake. Furthermore, the session will cover a systematic review of immunisation information systems (IISs) and the proposal of an innovative unvaccinated registry. This part of the workshop will delve into technological advancements and the integration of behavioural insights, which are essential for enhancing vaccine coverage and informing public health strategies. Another significant aspect of the discussion will be the evolution of vaccine mandates, from their historical roots to their contemporary applications. This discussion will reflect on policy shifts necessitated by emerging public health challenges and the need for adaptable strategies that can respond effectively to fluctuating vaccine coverage and acceptance rates. Panel discussions will feature notable experts such as Prof. Carlo Signorelli, President of the Italian NITAG, and Prof. Maria Ganczak, Vice President of the EUPHA Infectious Diseases Control section. These discussions will provide a comparative analysis of vaccination policies across different European countries, highlighting diverse approaches to mandates and the implementation of public health interventions aimed at combating vaccine hesitancy. By providing a unified approach to understanding and combating vaccine hesitancy, we aim to facilitate a critical exchange of ideas and strategies among experts in the field. It will serve as a dynamic platform for discussing evidence-based interventions tailored to specific population needs, enhancing public health outcomes across Europe. This engaging session promises to offer valuable insights into the complexities of vaccine hesitancy and the collaborative efforts required to address this global health challenge effectively. Key messages • Enhanced data collection and analysis are essential to combat vaccine hesitancy, allowing for tailored interventions that address specific community needs and barriers to vaccination. • Effective strategies against vaccine hesitancy require historical understanding and flexibility to adapt to new challenges, ensuring public health policies are responsive and culturally sensitive.

Clinical and immunological characteristics of COVID-19 in patients with disease dynamics

The aim is to study the clinical and immunological indicators of COVID-19 in the dynamics of the disease with the determination of predictors of the development of changes in the lungs. Materials and methods. The object of the study was 35 patients aged 22 to 75 years in the acute period and dynamics of COVID-19 disease, divided into two groups according to the identified clinical and immunological disorders. Markers of cellular (CD-3, CD-4, CD-8, CD-19) and humoral immunity, cytokines (IL-6,8, TGF-β, TNF-α), CEC were determined in all examined patients. Statistical processing of the obtained results was carried out using the computer program Statistica 10.0. Results. It was found that all the subjects retained clinical and immunological changes during the entire follow-up period, which indicates an ongoing disease. At the same time, significant differences in the severity of changes in individuals were revealed, taking into account age and the presence of chronic somatic pathology, expressed primarily in violation of the parameters of the T-system of immunity. In patients with the development of postcovoid changes in the lungs, characteristic immunological features were revealed, taking into account age. Conclusions. A violation of the detected indicators of the immune system may indicate the persistence of the virus, which means a prolongation of a specific inflammatory response with the risk of extensive tissue damage. Within three months after recovery, the tendency towards the formation of humoral immunity persists in both groups, which occurs by the end of 1 month after the disease in both groups and continues throughout the entire follow-up period. In the risk group for the development of pneumofibrosis in the outcome of a new coronavirus infection, the combination of IL-8 and TGF-β is the most optimal, despite their significant decrease in dynamics compared with the acute period.

Health-Related Parameterization Evaluating Thermal Comfort in Urban Green Spaces: Data Sourced from a Global Database and Mapping at National Scale

Outdoor thermal comfort (OTC) is one of the most important issues for people exposed to urban green space (UGS). It is mainly evaluated by assessing equivalent meteorological factors that may combine and result in human responses of perceptions about comfortable vs. uncomfortable environments. The assessment of these responses is challenged by limits in a database that is powerful enough to support big-data analysis and an essential parameter that can evaluate health-related responses to OTC in urban forests. In this study, a meta-analysis was conducted by synthesizing studies of physiological and psychological health responses of green space (GS) visitors to meteorological factors in host cities on a global scale. A total of 15,000 numerical records about the psychological and physiological responses of UGS visitors were obtained from 105 papers across 68 global cities in 21 countries. A novel parameterization was developed to evaluate OTC by normalizing changes in health-related parameters and detecting their regressions against multiple meteorological factors. It was revealed that OTC resulted in more benefits in psychological health parameters than in physiological ones for UGS visitors worldwide. Globally, health-promoting OTC environments were more found in temperate countries than in countries subjected to other climates. People in Asian countries were indicated to live in environments with higher comfort that benefitted health states in cities at low latitudes. Thermal environments tended to be harsher and more challenging, mostly too chilling, in northern cities than in the south globally. A deep learning model using the ResNet algorithm was found to perform to an expected level with R2 as high as >70% and errors controlled generally lower than 0.01. Taking mainland China for instance, it was predicted that thermal environments in eastern cities of China highly challenged the psychological health of local UGS visitors across all seasons of the year. Northern cities of China were predicted to have satisfied thermal environments that benefited psychological and psychological health responses in spring. In summer, cities in West China were predicted to have comfortable thermal environments, and in winter, environments in the southwestern cities were more comfortable.

MDA5 Is a Major Determinant of Developing Symptoms in Critically Ill COVID-19 Patients.

Apart from the skin and mucosal immune barrier, the first line of defense of the human immune system includes MDA5 (ifih1 gene) which acts as a cellular sensor protein for certain viruses including SARS-CoV-2. Upon binding with viral RNA, MDA5 activates cell-intrinsic innate immunity, humoral responses, and MAVS (mitochondrial antiviral signaling). MAVS signaling induces type I and III interferon (IFN) expressions that further induce ISGs (interferon stimulatory genes) expressions to initiate human cell-mediated immune responses and attenuate viral replication. SARS-CoV-2 counteracts by producing NSP1, NSP2, NSP3, NSP5, NSP7, NSP12, ORF3A, ORF9, N, and M protein and directs anti-MDA5 antibody production presumably to antagonize IFN signaling. Furthermore, COVID-19 resembles several diseases that carry anti-MDA5 antibodies and the current COVID-19 vaccines induced anti-MDA5 phenotypes in healthy individuals. GWAS (genome-wide association studies) identified several polymorphisms (SNPs) in the ifih1-ifn pathway genes including rs1990760 in ifih1 that are strongly associated with COVID-19, and the associated risk allele is correlated with reduced IFN production. The genetic association of SNPs in ifih1 and ifih1-ifn pathway genes reinforces the molecular findings of the critical roles of MDA5 in sensing SARS-CoV-2 and subsequently the IFN responses to inhibit viral replication and host immune evasion. Thus, MDA5 or its pathway genes could be targeted for therapeutic development of COVID-19.

B cell expression of the enzyme PexRAP, an intermediary in ether lipid biosynthesis, promotes antibody responses and germinal center size.

The qualities of antibody (Ab) responses provided by B lymphocytes and their plasma cell (PC) descendants are crucial facets of responses to vaccines and microbes. Metabolic processes and products regulate aspects of B cell proliferation and differentiation into germinal center (GC) and PC states as well as Ab diversification. However, there is little information about lymphoid cell-intrinsic functions of enzymes that mediate ether lipid biosynthesis, including a major class of membrane phospholipids. Imaging mass spectrometry (IMS) results had indicated that concentrations of a number of these phospholipids were substantially enhanced in GC compared to the background average in spleens. However, it was not clear if biosynthesis in B cells was a basis for this finding, or whether such cell-intrinsic biosynthesis contributes to B cell physiology or Ab responses. Ether lipid biosynthesis can involve the enzyme PexRAP, the product of the Dhrs7b gene. Using combinations of IMS and immunization experiments in mouse models with inducible Dhrs7b loss-of-function, we now show that B lineage-intrinsic expression of PexRAP promotes the magnitude and affinity maturation of a serological response. Moreover, the data revealed a Dhrs7b -dependent increase in ether phospholipids in primary follicles with a more prominent increase in GC. Mechanistically, PexRAP impacted B cell proliferation via enhanced survival associated with controlling levels of ROS and membrane peroxidation. These findings reveal a vital role of this peroxisomal enzyme in B cell homeostasis and the physiology of humoral immunity.

Growth factor dysregulation and placental dysfunction

The article is devoted to the study of angiogenic and antiangiogenic vascular growth factors in placental dysfunction, which is of great importance in obstetrics and perinatology. The study of growth factors as predictors of the development of placental dysfunction makes it possible to determine in advance the development of many obstetric pathologies, including preeclampsia and fetal growth retardation, which is of great practical importance. The authors conducted an immunological study of pregnant women with placental dysfunction and pregnant women with a physiological pregnancy. Purpose of the study: to study serum growth factors in women with placental dysfunction. We examined 47 pregnant women with a gestation period of 26-40 weeks, with a diagnosis of placental dysfunction, who were under observation in the obstetric department of the city maternity complex No. 3 of the city of Tashkent. The control group consisted of 35 women with a physiological pregnancy. All women underwent an immunological blood test: cellular and humoral immunity, as well as cytokines (VEGF-A, PlGF, sFlt-1, sFlt-1/PlGF) were studied. Based on the results obtained, the authors suggest that an increased level of soluble sFlt-1 and a simultaneous decrease in the levels of VEGF-A and PlGF in pregnant women at 26-40 weeks of gestation may portend the development of pregnancy complications, including preeclampsia and fetal growth restriction, and increase the risk of premature birth. Ddelivery due to impaired placental blood flow and oxygen deficiency for the fetus, lead to deterioration of microcirculation, and insufficient levels of VEGF-A and PlGF can contribute to vascular endothelial dysfunction, which can also contribute to the development of preeclampsia. The studied angiogenic and antiangiogenic vascular growth factors are important indicators and can serve as markers for predicting pregnancy complications for active medical intervention in maintaining the health of both mother and child.

Immunoreactivity Analysis of MHC-I Epitopes Derived from the Nucleocapsid Protein of SARS-CoV-2 via Computation and Vaccination

Background: Since 2019, the SARS-CoV-2 virus has been responsible for the global spread of respiratory illness. As of 1 September 2024, the cumulative number of infections worldwide exceeded 776 million. There are many structural proteins of the virus, among which the SARS-CoV-2 nucleocapsid (N) protein plays a pivotal role in the viral life cycle, participating in a multitude of essential activities following viral invasion. An important antiviral immune response is the major histocompatibility complex (MHC)-restricted differentiation cluster 8 (CD8+) T cell cytotoxicity. Therefore, understanding the immunogenicity of SARS-CoV-2 NP-specific MHC-I-restricted epitopes is highly important. Methods: MHC-I molecules from 11 human leukocyte antigen I (HLA-I) superfamilies with 98% population coverage and 6 mouse H2 alleles were selected. The affinity were screened by IEDB, NetMHCpan, SYFPEITHI, SMMPMBEC and Rankpep. Further immunogenicity and conservative analyses were performed using VaxiJen and BLASTp, respectively. EpiDock was used to simulate molecular docking. Cluster analysis was performed. Selective epitopes were validated by enzyme-linked immunospot (ELISpot) assay and flow cytometry in the mice with pVAX-NPSARS-CoV-2 immunization. Enzyme-Linked Immunosorbent Assay (ELISA) was used to detect whether the preferred epitope induced humoral immunity. Results: There were 64 dominant epitopes for the H-2 haplotype and 238 dominant epitopes for the HLA-I haplotype. Further analysis of immunogenicity and conservation yielded 8 preferred epitopes, and docking simulations were conducted with corresponding MHC-I alleles. The relationships between the NP peptides and MHC-I haplotypes were then determined via two-way hierarchical clustering. ELISA, ELISpot assay, and flow cytometry revealed that the preferred epitope stimulated both humoral and cellular immunity and enhanced cytokine secretion in mice. Conclusions: our study revealed the general patterns among multiple haplotypes within the humans and mice superfamily, providing a comprehensive assessment of the pan-MHC-I immunoreactivity of SARS-CoV-2 NP. Our findings would render prospects for the development and application of epitope-based immunotherapy in lasting viral epidemics.

Study of the state of humoral immunity to COVID-19 in Arkhangelsk residents

The COVID-19 pandemic caused by SARS-CoV-2 has affected healthcare, society and the economy in all countries, including Russia. Several vaccines have been created as the method for COVID-19 prevention. One of the most widespread vaccines in Russia, which has received international recognition, is the Gam-COVID-Vac (Sputnik V) vaccine and its variant Sputnik Light, which represents its first component. This vaccine, like similar vaccines in many countries, was used during the pandemic. The purpose of this work is to study the humoral immunity status of Arkhangelsk city residents and the effect of vaccination on them. Adult residents of Arkhangelsk [N = 281] were enrolled in the randomized study. Samples from vaccinated people and the control group were collected for the study in October 2022.The median from the time of last vaccination/booster to sample collection was 10 months. The samples were tested for the level of IgG to the receptor-binding domain of the SARS-CoV-2 S protein. The work assessed the humoral immunity status among residents of Arkhangelsk. It was shown that in October 2022 high IgG values were recorded among the people in the studied groups, most likely caused by contact with the SARS-CoV-2 virus. The humoral immunity status of unvaccinated residents, for those who have had COVID-19 and those who have not, is described; a significant increase in the level of IgG among those vaccinated compared to unvaccinated people is shown, despite the fact that the average time after vaccination was more than 10 months. A comparative analysis of IgG levels among different age groups was carried out. The study found no difference in post-vaccination antibody levels among people over 65 years old compared to younger age groups. Also there were no statistically significant differences in antibody levels among unvaccinated people over 65 in respect to younger age groups.

Experimental models of antibiotic exposure and atopic disease

In addition to numerous clinical studies, research using experimental models have contributed extensive evidence to the link between antibiotic exposure and atopic disease. A number of mouse models of allergy have been developed and used to uncover the specific effects of various microbiota members and perturbations on allergy development. Studies in mice that lack microbes entirely have also demonstrated the various components of the immune system that require microbial exposure. The importance of the early-life period and the mechanisms by which atopy “protective” species identified in human cohorts promote immune development have been elucidated in mice. Finally, non-animal models involving human-derived cells shed light on specific effects of bacteria on human epithelial and immune responses. When considered alongside clinical cohort studies, experimental model systems have provided crucial evidence for the link between the neonatal gut microbiota and allergic disease, immensely supporting the stewardship of antibiotic administration in infants. The following review aims to describe the range of experimental models used for studying factors that affect the relationship between the gut microbiota and allergic disease and summarize key findings that have come from research in animal and in vitro models.

When sounds come alive: animacy in the auditory sense

Despite the interest in animacy perception, few studies have considered sensory modalities other than vision. However, even everyday experience suggests that the auditory sense can also contribute to the recognition of animate beings, for example through the identification of voice-like sounds or through the perception of sounds that are the by-products of locomotion. Here we review the studies that have investigated the responses of humans and other animals to different acoustic features that may indicate the presence of a living entity, with particular attention to the neurophysiological mechanisms underlying such perception. Specifically, we have identified three different auditory animacy cues in the existing literature, namely voicelikeness, consonance, and acoustic motion. While the first two characteristics are clearly exclusive to the auditory sense and indicate the presence of an animate being capable of producing vocalizations or harmonic sounds—with the adaptive value of consonance also being exploited in musical compositions in which the musician wants to convey certain meanings—acoustic movement is, on the other hand, closely linked to the perception of animacy in the visual sense, in particular to self-propelled and biological motion stimuli. The results presented here support the existence of a multifaceted auditory sense of animacy that is shared by different distantly related species and probably represents an innate predisposition, and also suggest that the mechanisms underlying the perception of living things may all be part of an integrated network involving different sensory modalities.

A TLR7 Agonist Conjugated to a Nanofibrous Peptide Hydrogel as a Potent Vaccine Adjuvant.

Toll-like receptors (TLRs) recognize pathogen- and damage-associated molecular patterns and, in turn, trigger the release of cytokines and other immunostimulatory molecules. As a result, TLR agonists are increasingly being investigated as vaccine adjuvants. Many of these agonists are small molecules that quickly diffuse away from the vaccination site, limiting their co-localization with antigens and, thus, their effect. Here, the small-molecule TLR7 agonist 1V209 is conjugated to a positively-charged multidomain peptide (MDP) hydrogel, K2, which was previously shown to act as an adjuvant promoting humoral immunity. Mixing the 1V209-conjugated K2 50:50 with the unfunctionalized K2 produces hydrogels that retain the shear-thinning and self-healing physical properties of the original MDP while improving the solubility of 1V209 more than 200-fold compared to the unconjugated molecule. When co-delivered with ovalbumin as a model antigen, 1V209-functionalized K2 produces a robust Th2 immune response and an antigen-specific Th1 immune response superior to alum, a widely used vaccine adjuvant. Together, these results suggest that K2 MDP hydrogels functionalized with 1V209 are a promising adjuvant for vaccines against infectious diseases, especially those benefiting from a combined Th1 and Th2 immune response.